The invention disclosed herein employs or may employ some of the subject matter disclosed in commonly-owned U.S. patent Ser. No. 08/429,427 filed on Jul. 19, 1995 titled Collagen Compound Production in Plants. The disclosure of Ser. No. 08/429,427 is incorporated herein by reference.
The consumption of alcohol is rapidly increasing as leisure time increases and economic circumstances improve. Recent studies have shown that ninety percent of all Americans drink beverage alcohol, known chemically as ethanol. Between 40% to 50% of American men have a temporary alcohol-induced problem or display occasional drunkenness. Alcohol abuse by non-dependent persons involves patterns of considerable alcohol consumption associated with negative health consequences and/or impairment in social functioning. At least 10% of men and between 3%-5% of women are alcoholics or alcohol dependent. Alcohol dependence or alcoholism manifests itself in craving, tolerance and physical dependence that interfere with the ability to exercise restraint over drinking. Alcoholics display excessive alcohol consumption surpassing caloric or dietary needs or norms resulting in adverse health, social and economic consequences. Alcohol abuse and alcohol dependence (i.e., alcoholism) are serious worldwide public health problems. The international medical and economic cost of alcohol abuse. dependence and withdrawal are enormous; the social repercussions and psychological damage inflicted as a result of alcohol abuse on individuals, on children born with fetal alcohol syndrome, and on victims of alcohol-related accidental death, homicide and suicide are no less costly.
Ingested orally, ethanol is rapidly absorbed from the gastrointestinal tract into the circulatory system and diffuses readily and uniformly throughout the body's tissues and fluids. About 90% of the absorbed alcohol is metabolized in the liver. Alcohol may induce various toxic effects in the human body. Short term toxic effects include confused consciousness, ataxia, headache, vomiting, facial flushing, tachycardia, and heart palpitations. Long term effects of excessive alcohol intake include liver cirrhosis, alcohol liver disease, neurological abnormalities, depression of the immune system, alcoholic muscle disease, tissue damage, malnutrition weight loss, increased blood pressure and risk of cancer, predisposition to infectious diseases, and gastrointestinal disorders such as bleeding. Even individuals engaged in social drinking may develop lapses in mental impairment while driving or may even develop mild medical problems related to their drinking. For instance, blood alcohol levels between 0.5%-0.15% can cause decreased inhibitions of personality traits, slight visual impairment, slight muscular incoordination and slowing of reaction time (reflexes). Twenty -five percent of this group are clinically intoxicated. R. H. Dreisbach, Handbook of Poisoning, Lange Medical Publications, Los Altos, Calif., 1980.
On a biochemical and cellular level, alcohol acts as a continuous depressant of the central nervous system much like a general anesthetic. The apparent stimulation that individuals sense after alcohol ingestion results from the unrestrained activity of various parts of the brain that have been freed from inhibition by the alcohol as alcohol exerts its effects upon those parts of the brain, such as the cortex, involved in the most highly integrated functions. The first mental processes that are affected are those that depend on training and previous experience. In individuals ingesting alcohol, confidence initially abounds, the personality becomes expansive and vivacious and speech may become eloquent and occasionally brilliant. Mood swings are uncontrolled and emotional outbursts are displayed frequently. With respect to motor functions, alcohol affects both sensory and motor functions. Spinal reflexes are initially enhanced because they have been freed from central inhibition. Subsequently, these reflexes are impaired. In addition. intake of alcohol affects the efficacy of many classes of drugs. Drugs that interact negatively with alcohol include analgesic agents, oral hypoglycemic agents, and anticoagulants. Goodman and Gilman, The Pharmacological Basis of Therapeutics, McMillan Publishing Co., New York, pp. 137-142 (1990).
The adverse effects of alcohol consumption are due to ethanol, the main ingredient of alcohol. The level of ethanol in the blood is a major correlative factor in determining the adverse effects of alcohol. Ethanol is a weakly charged molecule that moves easily through and across cell membranes and rapidly equilibrates between the blood and tissues. After ingestion, small amounts of ethanol are absorbed from the mucus membranes of the mouth and esophagus into the blood. As the alcohol passes into the stomach, about 10% of the alcohol is absorbed from the stomach into the blood. The remaining alcohol of the digestive tract is absorbed by the small intestine. Once absorbed into the blood supply, a small amount (approximately 10%) is excreted out of the body via the lungs, urine or sweat. The remaining blood alcohol is metabolized by the liver to acetaldehyde by the enzyme alcohol dehydrogenase (ADH). The acetaldehyde is then rapidly converted to acetate/acetic acid in the liver by the enzyme aldehyde dehydrogenase (ALDH). The acetic acid is then converted to carbon dioxide and water. Each of these enzymatic steps requires oxidized nicotinomide adenine dinucleotide (NAD+) as a co-factor.
ADH is necessary in the metabolism of retinol or vitamin A, the production of rhodopsin, a vital protein in vision function, and the production of the male hormone, testosterone. Thus, chronic alcoholics often exhibit night blindness reflecting the lack of vitamin A metabolism. In addition, alcoholics may exhibit sterility and effeminization resulting from the decreased production of testosterone.
Many adverse effects of alcohol consumption may be related to the metabolism of alcohol to acetaldehyde by the liver. If acetaldehyde is formed and not further metabolized to acetate, it may cause liver and other tissue damage and toxicity. Acetaldehyde may also enter the blood stream and travel to the brain where it may block certain neurotransmitter activity causing changes in behavior, memory and motor functions. Alcoholism--The Biochemical Connection. Joan Mathews Larson, Ph.D., Willard Books, New York, 1992.
Both environmental and genetic factors influence the rate of alcohol degradation. People vary in their susceptibility to the toxic effects of alcohol due to differences in the biological activities of their ADH and ALDH enzymes. There is general agreement that alcoholism is a multifactorial disorder in which there is a significant genetic component, as illustrated by the twin and adoption studies performed over the past twenty years. Women have higher blood alcohol levels than men after consuming comparable amounts of ethanol. Frezza et al., N. Engl. J Med. 233:127-129 (1990). Men with an alcoholic biological parent are more than three times more likely to become alcoholic than are men with non-alcoholic biological parents. Several epidemiological surveys have shown that alcoholism is more prevalent in certain nationalities and racial groups than others. N. S. Cotton, J. Stud Alcohol 40:89-116 (1940). Other studies comparing alcoholism in identical versus fraternal twins highlight a genetic determinant. The molecular basis for a predisposition towards alcoholism is thought to be related to the various ways that alcohol is metabolized.
Oriental people respond differently than non-Oriental people to alcohol consumption, due, at least in part, to decreased ALDH activity, as described below. Additional factors may be involved such as the deficiency of .sigma.-ADH in the stomachs of Japanese subjects. Baraona et al., Life Sciences 49:1929-1934 (1991).
The human gastric ADH enzyme is complex, with ADHs of classes I, III and IV. Mareno et al., J. Biol Chem. 266:1128-1133 (1991). The main form of stomach ADH is a class IV .sigma.-ADH which exhibits an affinity toward ethanol much higher than that of the classical liver enzyme. Class IV .sigma.-ADH can metabolize between 10%-20% of the ethanol ingested. The ability to metabolize ethanol is assessed by measuring both the K.sub.m, V.sub.max and k.sub.cat values of an enzyme. K.sub.m, is equal to the substrate concentration (moles/liter) that results in one-half of the numerical maximum velocity (V.sub.max) of the enzyme. k.sub.cat is the maximal catalytic rate. Class IV .sigma.-ADH has an exceptionally high k.sub.cat value for ethanol. The k.sub.cat value of human class IV .sigma.-ADH is about 1000 at pH 7.5. The k.sub.cat value of classical human class I liver ADH is between 54 and 143 depending on isozyme. Thus, .sigma.-ADH processes ethanol about at least 10 to 20 times more efficiently than liver ADH. Current evidence suggests that in individuals consuming relatively high amounts of alcohol, it is the class IV .sigma.-ADH that probably is most responsible for metabolizing ethanol in the stomach.
Alcohol may begin being metabolized immediately upon entering the stomach. Any alcohol not metabolized in the stomach is absorbed from either the stomach or the small intestine and transported to the liver. Ethanol oxidation during this first cycle through the stomach, small intestine and liver is called "first-pass" metabolism.
Human class IV .sigma.-ADH has been detected in the mucosa of the upper digestive tract, specifically in the mouth, esophagus, stomach and in the cornea, but not in liver. Farres et al., Eur. J Biochem. 224, 549-557 (1994). This specific distribution suggests a distinct role for the class IV .sigma.-ADH enzyme, different from that of the hepatic ADH, i.e., it may be responsible, in part, for the first-pass metabolism of ingested ethanol in the stomach prior to its distribution into the systemic circulation.
With alcohol doses relevant to social drinking, stomach ADH acts as a barrier against toxic alcohol blood levels. The activity of stomach ADH correlates with the amount of alcohol metabolized by the stomach. In women, alcoholics, and patients treated with cimetidine, a drug used to treat stomach ulcers, the activity of stomach ADH is significantly reduced and more alcohol is absorbed into the blood. R. Gugler, Review! Drug Safety 10(4):271-280 (1994). Several other drugs, such as aspirin, inhibit the enzymatic activity of stomach ADH. Thus, subjects taking aspirin or cimetidine have increased blood alcohol levels, especially after repeated small drinks, which may result in unexpected impairment to perform complex tasks such as driving. Women under the age of 50 express significantly less activity of stomach ADH than age matched men. In addition, extremely low levels of these enzymes are found in young male alcoholics. Once these alcoholics abstained from alcohol for 2-3 weeks, their levels of stomach ADH returned to normal. Seitz et al., Gut, 34(10):1433-7 (1993). These studies concluded that the first-pass metabolism of alcohol is related to the activity of stomach class IV ADH. Similarly, studies by Frezza et al., N. Engl. J Med. 322(2):95-99 (1990) show that increased bioavailabilty of ethanol resulting from decreased stomach oxidation of ethanol may contribute to the enhanced vulnerability of women to acute and chronic complications of alcoholism.